Free Radicals - Michael Brooks [44]
When Alois Alzheimer first presented his new disease – in November 1906, at the 37th Meeting of South-west German Psychiatrists held in Tübingen – he focused on the case of a fifty-one-year-old woman who had suffered with memory loss, disorientation, depression and hallucinations. Her brain had atrophied in places, and there were ‘clumps of filaments between the nerve cells’. These are the ‘plaques’ that now characterise the disease.
In the brains of Alzheimer’s patients, chains of acid molecules come together to form long, sticky fibres of a substance known as beta amyloid that clump together in the brain. In 2009, researchers were excited to discover that normal prion proteins seem to interact with the beta amyloid fibres and stop them from forming into plaques. What’s more, research has also shown that human brain cells engineered to make more prion proteins also make less of the plaque-forming beta amyloid protein.
The link to Prusiner’s efforts is this: the overwhelming majority of researchers into prion disease now work on the assumption that the infection is caused by a prion protein that has taken on the wrong shape. And abnormal prion proteins – ones that have taken on the wrong shape – don’t offer any protection against the Alzheimer’s plaques.
Misfolding is not uncommon in proteins. Once formed, proteins usually fold themselves spontaneously into a variety of three-dimensional shapes, a little like self-creating origami. What started out as a long, boring string ends up, via a mechanism that remains a mystery to biologists, as an intricate sculpture of bends, waves and curves. This shape is central to the functions that protein will perform.
However, although they are remarkably robust – unfold some proteins, and they will fold themselves back into their proper shape – there are exceptions. The action of heat on egg-white protein is one: it unfolds and doesn’t return to its original shape as the egg cools. Instead, it forms a white, misfolded mass of protein that is rather good to eat.
Misfolding is rarely a good thing, though. Emphysema and cystic fibrosis are both the result of proteins that don’t fold as they should. And so, researchers suspect, are CJD, kuru and scrapie. If these diseases are caused by misfolded prion protein, it seems plausible that a lack of normal prion protein could also be linked to the formation of Alzheimer’s plaques.
It seems reasonable to suggest, then, that Alzheimer’s and these prion-borne diseases might be somehow connected. In fact, it seems more than reasonable. But although the link between Alzheimer’s and Prusiner’s prion diseases might look like an open and shut case, it is not. We don’t yet understand how (or whether, for that matter) prion protein really is involved in diseases such as kuru and CJD. Our best guess is that they involve prion proteins that have somehow folded up differently to normal; this mis-folded protein then encourages natural prion proteins to fold in the wrong way, leading to the spread of disease. But we don’t know that for sure. It’s promising that researchers have made misshapen prions in a test tube and injected them into mice that then went on to develop CJD-like disease. However, it only happened in mice that were genetically engineered to produce huge amounts of prion protein in their brains. Normal mice remained perfectly healthy.
The prion-protein-only idea also fails to explain why different strains of the prion diseases appear from the same infective dose: one mouse might become hyperactive, for instance, while another becomes drowsy. Though misfolded prion protein seems to be involved in whatever is causing these diseases, it also seems to be only part of the answer.